Quercetin activates the SIRT6-Nrf2 axis during oxidative stress, modulating DNA repair and ageing-associated markers

Quercetin is a dietary flavonoid with antioxidant, anti-inflammatory, and senolytic properties, yet its effects on exercise-induced DNA damage responses in healthy humans are unclear. We conducted a double-blind, placebo-controlled crossover trial (n = 13, middle-aged men) combining acute high-intensity interval exercise (HIIE) with 21-day quercetin supplementation (1000 mg/day). We quantified plasma quercetin and nuclear localisation, DNA repair and sirtuin gene expression, oxidative DNA damage (single and double-strand breaks, oxidised purines), and plasma/IgG glycomics including a preliminary GlycanAge index. Quercetin increased in plasma and nucleus post-exercise (p < 0.001; p < 0.05). Compared with placebo, quercetin increased post-exercise SIRT6-quercetin nuclear colocalisation (p < 0.001 at all timepoints) and Nrf2 nuclear translocation (p < 0.001). In placebo, SIRT1, PARP1 and RAD51 expression increased post-exercise, whereas SIRT6 and OGG1 decreased; this pattern was reversed with quercetin (all p < 0.05). Oxidative DNA damage markers were reduced with quercetin versus placebo (p < 0.001). Exercise-induced increases in plasma galactosylation and decreases in agalactosylation were observed in placebo but not with quercetin (all p < 0.05); GlycanAge showed non-significant increases post-exercise in placebo and a non-significant decrease following 21-day quercetin supplementation. In summary, short-term quercetin activates a SIRT6-Nrf2-linked response during HIIE, sustains DNA repair capacity, and stabilises inflammatory glycomic dynamics, consistent with a shift toward energetically economical, chromatin-associated repair. By providing evidence that quercetin biases DNA repair pathway usage under physiological oxidative stress, this work advances a framework of repair efficiency and energetic economy in human genome maintenance. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=144 HEIGHT=200 SRC="FIGDIR/small/25338366v4_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@e61897org.highwire.dtl.DTLVardef@589127org.highwire.dtl.DTLVardef@a19ab2org.highwire.dtl.DTLVardef@1b32cda_HPS_FORMAT_FIGEXP M_FIG C_FIG Ageing and high-intensity interval exercise (HIIE) engage overlapping oxidative stress, DNA damage, and inflammatory signalling pathways, but with distinct temporal profiles. Acute HIIE induces reactive oxygen species (ROS) and increases peripheral blood mononuclear cell (PBMC) expression of stress-responsive DNA damage response genes PARP1, SIRT1, and RAD51, whereas SIRT6, OGG1, and nuclear Nrf2 are selectively increased with quercetin supplementation. Exercise-induced plasma N-glycosylation remodelling--characterised by increased galactosylation and reduced agalactosylation--was observed after HIIE but was abolished by quercetin supplementation, indicating stabilisation of glycosylation dynamics under reduced oxidative signalling. GlycanAge (an inflammaging index) exhibited only non-significant acute changes but may require longer-term supplementation to shift measurably. Dashed arrows indicate inferred or integrative relationships.